Nalmefene hydrochloride dihydrate

ABSTRACT

The present invention relates to the Nalmefene hydrochloride dihydrate, methods of manufacturing Nalmefene hydrochloride dihydrate, a pharmaceutical composition comprising Nalmefene hydrochloride dihydrate and a method of treatment comprising administering Nalmefene hydrochloride dehydrate.

The present invention relates to a novel non-hygroscopic form ofNalmefene Hydrochloride, namely Nalmefene hydrochloride dihydrate, inparticular for oral dosage forms, and methods for its production.

BACKGROUND

Nalmefene is a known opioid receptor antagonist which can inhibitpharmacological effects of both administered opioid agonists andendogenous produced agonists from the opioid system. The clinicalusefulness of Nalmefene as an antagonist comes from its ability topromptly (and selectively) reverse the effects of these opioid agonists,including the often observed depressions in the central nervous systemand the respiratory system.

Nalmefene has primarily been developed for use in the management ofalcohol dependence, where it has shown good effect in doses of 10 to 40mg taken when the patient believed drinking to be imminent (about 1-2hours before drinking) (Karhuvaara et al., Alcohol. Clin. Exp. Res.,(2007), Vol. 31 No. 7. pp 1179-1187). Additionally, Nalmefene has alsobeen investigated for the treatment of other addictions such aspathological gambling and addiction to shopping. In these developmentalprograms and testing, Nalmefene has been used, for example as a parentalsolution (Revex™).

Nalmefene is an opiate derivative similar in structure to the opiateantagonist Naltrexone. Advantages of Nalmefene relative to Naltrexoneinclude longer half-life, greater oral bioavailability and no observeddose-dependent liver toxicity.

Nalmefene differs from Naltrexone by substitution of the ketone group atthe 6-position of Naltrexone with a methylene (CH₂) group, whichconsiderably increases binding affinity to the μ-opioid receptor.Nalmefene also has high affinity for the other opioid receptors (κ and δreceptors), and is known as a “universal antagonist” for its ability toblock all three.

Nalmefene can be produced according to the method described by Hahn etal. (J. Med. Chem., 18, 259-262 (1975), Mallinekrodt (U.S. Pat. No.4,751,307), and Meltzner et al., (U.S. Pat. No. 4,535,157).

By using the above-mentioned methods, the free base of Nalmefene isobtained, which subsequently can be converted into the hydrochloridesalt, by use of conventional methods.

According to Brittain, (Analytical Profiles of Drug Substances andExcipients (1996), Vol 24, pp. 351-395) Nalmefene hydrochloride can berecrystallized from water, giving a pure drug substance, whichinevitably consists of a monohydrate crystal phase. In the same reviewthe monohydrate phase of Nalmefene hydrochloride is described asessentially non-hygroscopic since it can only sorb up to 1% ofadventitious moisture.

The inventors of the present invention have found that, contrary to theliterature, Nalmefene hydrochloride as a monohydrate is hygroscopic.

There is therefore a need for providing a novel, stable andnon-hygroscopic hydrate form of Nalmefene and methods for itsmanufacturing.

SUMMARY OF THE INVENTION

The present invention relates to Nalmefene hydrochloride dihydraterepresented by the formula

preferably in a crystalline form. Said Nalmefene hydrochloride dihydrateis non-hygroscopic

The invention further relates to two methods of producing Nalmefenehydrochloride dihydrate:

-   -   Method (I): transformation of Nalmefene hydrochloride into        Nalmefene hydrochloride dihydrate by re-slurry in aqueous        solution, exemplified by water, such as pure water, and    -   Method (II): recrystallisation of Nalmefene hydrochloride in        aqueous solution, exemplified by water, such as pure water.

The re-slurry method (Method I) comprises the steps of:

-   -   (1) mixing Nalmefene Hydrochloride        (17-(cyclopropylmethyl)-4,5-α-epoxy-6-methylenemorphinan-3,14-diol        hydrochloride) and aqueous solution, exemplified by water, such        as pure water,    -   (2) optionally, heating the mixture,    -   (3) optionally, distilling the mixture,    -   (4) stirring the mixture until transformation is complete, such        as less than 1 hour, such as about 1 hour, such as for at least        1 hour, and    -   (5) isolating the formed solid.

The re-crystallisation method (Method II) comprises the steps of:

-   -   (a) mixing Nalmefene hydrochloride        (17-(cyclopropylmethyl)-4,5-α-epoxy-6-methylenemorphinan-3,14-diol        hydrochloride) and aqueous solution, exemplified by water, such        as pure water,    -   (b) heating of the mixture to obtain a substantially homogenous        solution,    -   (c) optionally, distillation of the mixture obtained in (b).    -   (d) cooling of the solution obtained in step (b) or (c),        subsequently seeding with Nalmefene hydrochloride, and    -   (e) isolation of the formed solid.

A further aspect of the present invention (Method III) is a method torecover any unused Nalmefene from the methods I and II, comprising thesteps of:

-   (i) optionally, distillation of mother liquors obtained from    method (I) or (II)-   (ii) basification of the mother liquors obtained in step (i), or    from the methods (I) or (II),-   (iii) extracting the mixture with a suitable organic solvent,-   (iv) adding hydrogen chloride, and-   (v) isolating the formed solid

The invention further relates to pharmaceutical compositions comprisingNalmefene hydrochloride dihydrate, the use of Nalmefene hydrochloridedihydrate in medicine, and in particular the use of Nalmefenehydrochloride dihydrate for the treatment of alcohol dependency.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Shows TGA thermogram of the Nalmefene hydrochloride dihydrate.The y-axis shows the percentage in mass, and the X-axis showstemperatures (° C.).

FIG. 2 Shows DVS experiments performed at 40° C. of Nalmefenehydrochloride dihydrate (dry plot). The first y-axis (left) show thechange in mass relative to anhydrous (%), and the other y-axis (right)displays the targeted relative humidity (RH)(%), while the x-axis showthe time in minutes. The thin line shows the changes in target RH, andthe bold line the changes in relation to mass.

FIG. 3 Shows X-ray powder diffractogram of the Nalmefene hydrochloridedihydrate. The y-axis shows the intensity (counts), and the x-axis showsthe 2Theta angle (°).

FIG. 4 Shows TGA thermogram of the Nalmefene hydrochloride monohydrate.The y-axis shows the percentage in mass, and the x-axis showstemperatures (° C.).

FIG. 5 Shows DVS experiments performed at 40° C. of Nalmefenehydrochloride monohydrate (dry plot). The first y-axis (left) show thechange in mass relative to anhydrous (%), and the other y-axis (right)displays the targeted relative humidity (RH)(%), while the x-axis showthe time in minutes. The thin line shows the changes in target RH, andthe bold line the changes in relation to mass.

FIG. 6 Shows X-ray powder diffractogram of the Nalmefene hydrochloridemonohydrate. The y-axis shows the intensity (counts), and the x-axisshows the 2Theta angle(°).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to Nalmefene hydrochloride dihydraterepresented by the below formula

The dihydrate form of Nalmefene hydrochloride is particular advantageousin that it is non-hygroscopic. As a result of this non-hygroscopicfeature, the physical properties can more easily be controlled. This isof great importance when preparing solid dosage forms such as orallyadministrable forms, including solid unit dosage forms e.g. tablets orchewable tablet and capsules.

As is well known within the pharmaceutical industry, processing ofhygroscopic products entails the use of controlled humidity chambersboth for storage and for the processing itself. Moreover, the finishedhygroscopic products must be packed in sealed blisters in order to avoidstability problems due to humidity. These disadvantages are avoided byusing Nalmefene hydrochloride as the non-hygroscopic dihydrate.

Nalmefene hydrochloride dihydrate is characterized by beingnon-hygroscopic and stable in its water content. The compound does notabsorb or lose water when exposed to a relative humidity (RH) of between10% and 95%.

As shown in Example 1 of the present invention, DVS (Dynamic VapourSorption) experiments were performed at 25° C. and at 40° C. The resultsshowed that no water was absorbed by Nalmefene hydrochloride dihydrateeven at 95% RH. In contrast hereto, as shown in Example 2, Nalmefenehydrochloride as monohydrate absorbed about 2.5% water when exposed to95% RH and 40° C.

Furthermore, the result in Example 2 showed that in contrast to thedihydrate, the monohydrate form changes in the water content with thesurrounding humidity, and at RH above 50% the monohydrate form changedinto a new structure with higher water content.

It is therefore an important characteristic of Nalmefene hydrochloridedihydrate that it is non-hygroscopic, as defined above. Thus the presentinvention relates to Nalmefene hydrochloride dihydrate which isnon-hygroscopic, meaning that less than 1%, such as less than 0.5%, suchas less than 0.3% moisture is absorbed when exposed to 95% RH at 25° C.

Nalmefene hydrochloride dihydrate is a crystalline solid characterizedby X-ray reflections at angles 8.99, 10.63, 15.24, 16.55 and 17.20°2θ(±0.1°2θ) as measured using CuK_(α1) radiation, and having water contentof about 8 to about 9%, such as about 8.7%, while the monohydrate ofNalmefene hydrochloride is a crystalline solid characterized by X-rayreflections at angles 7.39, 11.33, 11.52, 17.70 and 24.27°2θ (±0.1°2θ)and water content of 4-7% depending on the relative humidity of thesurroundings.

The present invention also relates to the use of Nalmefene hydrochloridedihydrate in the manufacturing of a medicament.

In particular, the invention is related to the use of Nalmefenehydrochloride dihydrate in the manufacturing of a medicament, whereinNalmefene hydrochloride dihydrate comprises at least 5% (w/w), such asat least 10% (w/w), at least 30%, at least 50% (w/w), such as at least70% (w/w), at least 90% (w/w), at least 95% (w/w), at least 99% (w/w),or 100% of the pharmaceutical dosage form, particularly a oral dosageform, e.g. a single unit solid dosage form such as a tablet. Nalmefenehydrochloride dihydrate is in particular related to the use in themanufacturing of a medicament for the treatment alcohol dependency.

In a further embodiment, the present invention relates to a method fortreating alcohol dependency comprising administering a therapeuticallyeffective amount of Nalmefene hydrochloride dihydrate, e.g. in apharmaceutical composition (such as a solid dosage form, e.g. tablet fororal administration) to a patient in the need thereof.

By the term “therapeutically effective amount” is referred to theamount/dose of a compound or pharmaceutical composition that issufficient to produce an effective response (i.e., a biological ormedical response of a tissue, system, animal or human sought by aresearcher, veterinarian, medical doctor or other clinician) uponadministration to a patient. The “therapeutically effective amount” willvary depending on inter alia the disease and its severity, and the age,weight, physical condition and responsiveness of the patient to betreated. Furthermore the “therapeutically effective amount” may vary ifthe compound of the invention is combined with one or more compounds, insuch a case the amount of a given compound might be lower, such as asub-effective amount.

The term ‘distil’ refers to a method of separating mixtures based ondifferences in their volatilities in a boiling liquid mixture.Application of vacuum such as partial vacuum is an example of suchseparation method.

The term ‘chemical purity’ is given its normal meaning within the artand thus refers to the degree to which an obtained compound iscontaminated with impurities. Accordingly, an obtained compound which isat least 98% chemically pure comprises at most 2% of impurities. Thechemical purity may be measured by e.g. HPLC.

The term ‘assay’ refers to the effective content of the desiredsubstance expressed as a weight by weight percentage (w/w %).

The term ‘extraction’ refers to a liquid-liquid extraction in which thefree Nalmefene base is transferred from an aqueous phase to an organicphase.

The term ‘re-slurry’ refers to a process wherein the crystallinematerial is suspended in a solvent or a solvent mixture at anappropriate temperature whereby the crystalline material partiallydissolves and partially crystallises again thus permitting itstransformation into the desired form and/or its purification.

KF refers to ‘Karl Fisher titration’.

TGA refers to ‘Thermo-Gravimetric Analysis’.

DVS refers to ‘Dynamic Vapour Sorption’

In the present invention, the term “substantially homogenous solution”is intended to mean a liquid mixture free of visible undissolvedmaterial.

In the present invention, the term “seeding” is intended to mean theaddition of a small amount of crystals to initiate the precipitation ofthe product.

In the present context the term “non-hygroscopic” is intended to meanthat less than 1%, such as less than 0.5%, such as less than 0.3% w/w ofmoisture is absorbed when exposed to 95% RH at 25° C.

In the present context, particle sizes are determined by LaserDiffraction using a Malvern Mastersizer S instrument as disclosed indetails in the introductory part of the experimental section.

Preferably the amount of Nalmefene hydrochloride dihydrate in apharmaceutical composition is in an amount from about 10 mg to about 100mg, such as about 10 mg to about 60 mg, about 10 mg to about 40 mg, orabout 20 mg.

The term “alcohol dependency” is a commonly known term for a skilledperson which, in the revised 4th edition of the Diagnostic andStatistical Manual of Mental Disorders (DSM-IVTR) (Diagnostic andStatistical Manual of Mental Disorders, 4th edition text revision,American Psychiatric Publishing, 2000), is defined as the presence ofthree or more of the seven areas of life impairment related to alcoholin the same 12-month period. These impairments include tolerance,evidence of a withdrawal syndrome when alcohol is discontinued or intakeis decreased, potential interference with life functioning associatedwith spending a great deal of time using alcohol and returning to usedespite evidence of physical or psychological problems.

The pharmaceutical composition comprising Nalmefene hydrochloridedihydrate may further comprise one or more pharmaceutically acceptablecarriers.

Methods for the preparation of solid pharmaceutical preparations arewell known in the art. See, e.g., Remington: The Science and Practice ofPharmacy, 21st ed., Lippincott Williams & Wilkins (2005). Solidpreparations, such as tablets, may be prepared by mixing the activeingredients with an ordinary carrier, such as an adjuvant and/ordiluent, and subsequently compressing the mixture in a tablettingmachine. Non-limiting examples of adjuvants and/or diluents include:corn starch, lactose, talcum, magnesium stearate, gelatine, lactose,gums, and the like. Any other adjuvant or additive such as colourings,aroma, and preservatives may also be used provided that they arecompatible with the active ingredients. The pharmaceutical compositionsof the invention thus typically comprise an effective amount ofNalmefene hydrochloride dihydrate and one or more pharmaceuticallyacceptable carriers.

According to the present invention, it is envisaged that Nalmefenehydrochloride dihydrate may be administered in any suitable way, e.g.,orally or parenterally, and it may be presented in any suitable form forsuch administration, e.g., in the form of tablets, capsules, powders,syrups or solutions or dispersions for injection. In an embodiment,Nalmefene hydrochloride dihydrate is preferably administered in the formof a solid pharmaceutical entity, suitably as a tablet or a capsule.

A further aspect of the present invention relates to methods forobtaining Nalmefene hydrochloride dihydrate. Nalmefene hydrochloridedihydrate may be obtained by any of the methods (I) and (II), as will beoutlined below.

-   -   Method (I) transformation of Nalmefene hydrochloride into        Nalmefene hydrochloride dihydrate by re-slurry in aqueous        solution, such as water, such as pure water and    -   Method (II) re-crystallization of Nalmefene hydrochloride in        aqueous solution, such as water, such as pure water

According to One Aspect of the Invention, the Re-Slurry Method (Method(I))

comprises the steps of:

(1) mixing Nalmefene Hydrochloride(17-(cyclopropylmethyl)-4,5-α-epoxy-6-methylenemorphinan-3,14-diolhydrochloride) and aqueous solution, such as water, such as pure water(2) optionally, heating the mixture,(3) optionally, distilling the mixture(4) stirring the mixture, and(5) isolating the formed solid.

In one embodiment of Method (I), Nalmefene hydrochloride is transformedinto Nalmefene hydrochloride dihydrate by re-slurry in aqueous solution.In another embodiment Nalmefene hydrochloride is transformed intoNalmefene hydrochloride dihydrate by re-slurry in water. In yet anotherembodiment Nalmefene hydrochloride is transformed into Nalmefenehydrochloride dihydrate by re-slurry in pure water.

The ratio of aqueous solution such as water, such as pure water, used instep (1) may range from about 0.5 ml to about 4 ml aqueoussolution/nalmefene hydrochloride (g), such as from about 1 ml to about 2ml aqueous solution/nalmefene hydrochloride (g), more preferably about1.5 ml aqueous solution/nalmefene hydrochloride (g). The Nalmefenehydrochloride used can be selected from any hydrated or solvated form ofNalmefene or mixtures of hydrated and/or solvated forms with or withoutsolvents. In one embodiment Nalmefene hydrochloride as monohydrate isused. In another embodiment of Method (I), Nalmefene hydrochloride isused in hydrated form. In another embodiment, Nalmefene hydrochloride isused in solvated form. In yet another embodiment, Nalmefenehydrochloride is used in a mixture of hydrated solvated form.

In an embodiment of Method (1), solvents comprised in said hydratedand/or solvated forms are selected from the group consisting of acetone,n-propanol, isopropanol, dichloromethane and water. In one embodimentsaid solvent is acetone. In another embodiment said solvent isn-propanol. In yet another embodiment said solvent is isopropanol. Inyet another embodiment said solvent is dichloromethane. In yet anotherembodiment said solvent is water.

Heating in step (2) is an optional step, which may under some conditionsbe beneficial in order to increase the dissolution rate of the mixtureobtained in step (b). The heating temperature may depend on thecircumstances. Under some circumstances the mixing will be efficientlyperformed at room temperature (20-25° C.). It is envisaged that in oneembodiment heating in step (2) is to about 50° C. In another embodiment,heating in step (2) is to 50° C. or less. In another embodiment heatingto in step (2) is to about 20° C. to about 40° C. In yet anotherembodiment heating in step (2) is to about 30° C.

Step (2) and step (3) may be performed with or without stirring.

The distillation in step (3) may be performed to remove organic solventsif present in the mixture. The distillation may be performed by applyingVacuum.

The stirring in step (4) may be performed at a temperature of about 0°C. to about 50° C., such as 45° C., such as from 20° C. to about 40° C.In one embodiment, the mixture is stirred for less than one hour. Inanother embodiment the mixture is stirred for about one hour. In yetanother embodiment the mixture is stirred for at least one hour.

The solid can be isolated at a temperature within the range of about0-25° C. such as 0-20° C. and more preferably in the range of 0-5° C. inorder to lower the solubility of the product, such as in water, and toincrease the yield. The solid may be isolated by filtration and washedwith a suitable solvent. Solvents for washings include water andmixtures of water/organic solvents or pure organic solvents. Preferablywater is used and in a further embodiment pre-cooled water is preferred.When organic solvents are used, Class 2 or 3 solvents (ICH Q3C(R4)guidelines) are preferred. In one embodiment, class 3 solvents such asacetone and ethyl acetate are used. In one embodiment acetone is used.In another embodiment ethyl acetate is used.

The product can be dried under vacuum below 40° C. and more preferablyat a temperature in the range 25-35° C.

It is envisaged that the obtained compound is at least 98% chemicallypure, such as at least 99% chemically pure, or at least 99.5% chemicallypure.

According to One Aspect of the Invention, the Re-Crystallization Method(Method (I))

comprises the steps of:

-   -   (a) mixing Nalmefene hydrochloride        (17-(cyclopropylmethyl)-4,5-α-epoxy-6-methylenemorphinan-3,14-diol        hydrochloride) and aqueous solution, such as water, such as pure        water,    -   (b) heating the mixture to obtain a substantially homogenous        solution,    -   (c) optionally, distillation of mixture obtained in step (b),    -   (d) cooling of the solution obtained in step (b) or (c),        subsequently seeding with Nalmefene hydrochloride, and    -   (e) isolation of the formed solid.

In one embodiment of Method (II), Nalmefene hydrochloride is transformedinto Nalmefene hydrochloride dihydrate by re-crystallization in aqueoussolution. In another embodiment Nalmefene hydrochloride is transformedinto Nalmefene hydrochloride dihydrate by re-slurry in water. In yetanother embodiment Nalmefene hydrochloride is transformed into Nalmefenehydrochloride dihydrate by re-slurry in pure water.

The amount of aqueous solution, such as water, such as pure water, whichis used in step (a) may range from about 0.9 ml to about 4 ml aqueoussolution/Nalmefene hydrochloride (g), such as from about 1 ml to about 2ml aqueous solution/Nalmefene hydrochloride (g), or about 1.5 ml aqueoussolution/Nalmefene hydrochloride (g). The Nalmefene hydrochloride usedcan be selected from any hydrated or solvated form of Nalmefene ormixtures of hydrated and/or solvated forms with or without solvents.

In one embodiment of Method (II), Nalmefene hydrochloride is used inhydrated form. In another embodiment, Nalmefene hydrochloride is used insolvated form. In yet another embodiment, Nalmefene hydrochloride isused in a mixture of hydrated solvated form.

In an embodiment of Method (II), solvents comprised in said hydratedand/or solvated forms are selected from the group consisting of acetone,n-propanol, isopropanol, dichloromethane and water. In one embodimentsaid solvent is acetone. In another embodiment said solvent isn-propanol. In yet another embodiment said solvent is isopropanol. Inyet another embodiment said solvent is dichloromethane. In yet anotherembodiment said solvent is water.

The suspension may be heated until a substantially homogenous solutionis obtained, i.e. a solution. The heating in step (b) may be performedto reach a temperature of about 50° C. to about 100° C., such as about50° C. to about 90° C., or about 70° C. to about 85° C.

Partial vacuum may then applied to remove traces of organic volatiles,if present, in step (c).

The solution obtained either from step (b) or step (c) may optionally befiltered (e.g. through a 0.65 μm cartridge) to remove foreign mattersbefore proceeding to step (d).

In step (d) the solution may be cooled to a temperature between 40° C.to about 50° C. and seeded. In one embodiment of the invention, theseeding is performed at a temperature between 40° C. and 50° C. Theseeding is performed with Nalmefene hydrochloride dihydrate crystals.The Nalmefene seeding material may, in one embodiment of the invention,be obtained by the re-slurry method (I) described above.

The amount of seed crystal added in step (d) may be from about 1/2000(w/w) of seed crystal of Nalmefene hydrochloride/Nalmefene hydrochlorideadded in step (a), such as from about 1/1000 (w/w) of seed crystal or1/200 of seed crystal of Nalmefene hydrochloride/Nalmefene hydrochlorideadded in step (a).

An appropriate cooling ramp, such as a fast cooling ramp, and anappropriate stirring, such as a vigorous stirring, impede the crystalsalready formed to grow further and help to provide a product with a welldefined, narrow and relatively small particle size. The cooling fromseeding temperature to isolation temperature may be accomplished withina few hours and more preferably within 1 hour. The seeded mixtureobtained in step (d) may therefore further be subjected to a cooling,such as a fast cooling, which comprises the steps of:

(d′) a further cooling of the mixture to a temperature of about 0-5° C.such as over a time period of about 45 minutes or more, and(d″) thereafter the mixture may be maintained at a temperature of about0-5° C. for e.g. about 45 minutes or more before isolating the formedsolid according to step (e).

The solid formed in step (c) may be isolated. The solid can be isolatedat a temperature within the range of about 0-20° C. and more preferablyin the range of 0-5° C. in order to lower the solubility of the productin water and thereby increase the yield. The solid may be isolated byfiltration and washed with a suitable solvent. Solvents for washingsinclude water and mixtures of water/organic solvents or pure organicsolvents. In one embodiment solvents for washing are selected from thegroup consisting of acetone and water. In one embodiment acetone isused. In another embodiment a mixture of acetone and water. In yetanother embodiment water is used. In a further embodiment the water usedis pre-cooled water. When organic solvents are used for washing, Class 2or 3 solvents (ICH Q3C(R4) guidelines) are preferred, more preferablyclass 3 solvents such as acetone and ethyl acetate. In one embodimentethyl acetate is used.

The product can be dried under vacuum below 40° C. and more preferablyat a temperature in the range 25-35° C.

It is envisaged that the obtained compound is at least 98% chemicallypure, such as at least 99% chemically pure, or at least 99.5% chemicallypure.

It is further envisaged that the Nalmefene hydrochloride dihydrateobtained by the above method (II) has the following particle sizedistribution: D90 equal to or below 400 μm and D50 equal to or below 200μm, and D10 equal to or below 50 μm, and with ratio D90/D50 equal to orbelow 2.5, wherein D″XX″ (XX is given as 10, 50 or 90) is defined as thevalue for which an “XX percentage” (given in volumes) of the particleshave a diameter under the indicated value. Thus for D10, 10 percentageof the particle size (in volume) has a diameter equal to or below 50 μm.

Recovery of Nalmefene Hydrochloride from Mother Liquors (Method III):

Nalmefene hydrochloride is highly soluble in aqueous solutions such aswater, such as pure water, and therefore a part of this material is lostin the mother liquors. To recover any unused Nalmefene hydrochloridefrom the methods I or II, outlined above, a method for the recovery hasbeen developed that comprises

-   (i) optionally, distillation of mother liquors obtained from    method (I) or (II)-   (ii) basification of the mother liquors obtained in step (i), or    from the methods (I) or (II),-   (iii) extracting the mixture with a suitable organic solvent,-   (iv) adding hydrogen chloride, and-   (v) isolating the formed solid

The basification in step (ii) is performed to bring the pH in the rangeof 8-10, such as 8-9 using an organic or inorganic base. In anembodiment of method (III), the basification in step (ii) is performedwith ammonium hydroxide.

In the extraction step (iii) the organic solvent may be selected fromthe group comprising halogenated hydrocarbons, ethers, esters, ketones,and preferably dichloromethane, 2-methyl-tetrahydrofurane, ethylacetate, 2-butanone, even more preferably dichloromethane. In oneembodiment the organic solvent is halogenated hydrocarbons. In anotherembodiment the organic solvent is ethers. In another embodiment theorganic solvent is selected from the group of esters. In anotherembodiment the organic solvent is selected from the group of ketones. Inanother embodiment the organic solvent is dichloromethane. In anotherembodiment the organic solvent is 2-methyl-tetrahydrofurane. In anotherembodiment the organic solvent is ethyl acetate. In another embodimentthe organic solvent is 2-butanone.

The solution of nalmefene base in an organic solvent obtained in step(iii) is treated with hydrogen chloride to precipitate nalmefenehydrochloride.

The amount of hydrogen chloride added in step (iv) depends on differentfactors such as the amount of nalmefene in mother liquors used, and willbe apparent to a person skilled in the art. After hydrochloric acid isadded to the mixture in step (iv) the product is allowed to precipitate.

The precipitated solid may be isolated as described for methods I andII.

It is envisaged that the obtained compound is at least 98% chemicallypure, such as at least 99% chemically pure, or at least 99.5% chemicallypure.

EXAMPLES

In the present contest, chemical purity is measured by HPLC using thebelow conditions:

Chromatographic Conditions:

-   Column: . . . YMC Basic B-03-5, 5 μm, 250×4.6 mm or equivalent-   Mobile Phase A: . . . Buffer-   Mobile Phase B: . . . Methanol-   Buffer: . . . Dissolve 1.1 g of Sodium Octansulfonate (FW 216.28) in    1 L of water. Adjust the pH to 3.8 with diluted H₃PO₄.-   Column Temperature: . . . 35° C.-   Detector: . . . UV at 230 nm-   Flow: . . . 1.5 ml/min-   Injection volume: . . . 20 μl-   Time of Analysis: . . . 50 minutes

Time (min) Mobile Phase A Mobile PhaseB 0 90 10 10 70 30 25 50 50 40 2080 50 20 80

In the present context, particle sizes are determined by LaserDiffraction using a Malvern Mastersizer S instrument made up of a lasertransmitter (LASER HELIUM-NEON-wavelength 632 nm), an optical system(300 F lens, range 0.5-900 μm), a measurement cell for suspension (beamlength 2.4 mm) and a photodiode detector. The sample is analysed usingmineral oil (CAS 8042-47) as dispergent.

Example 1 1.1a Preparation of the Dihydrate

Dihydrate was prepared as follows:

20 g of crude Nalmefene Hydrochloride (chemical purity 99.26%, assay92.9%) was suspended in 24 ml of water. The mixture was heated up andthe solid dissolved completely at 60-65° C. The solution was heated upto 70° C. and maintained at that temperature for 15 minutes. Thesolution was cooled down from 70° C. to 20° C. in 3 hours using a linearramp.

At 50° C., Nalmefene Hydrochloride was added as seeding. The seed didnot dissolve and Nalmefene started to crystallize. When the cooling rampwas terminated the suspension was maintained under stirring at 20° C.for 2.5 days. The solid was filtered and washed with acetone (50 ml).The wet product was dried overnight under vacuum at 40° C. yielding 13.2g of Nalmefene hydrochloride dihydrate (chemical purity 99.74%, watercontent 8.54% w/w as measured by Karl Fisher titration).

1.1b Preparation of the Dihydrate

20 g of crude Nalmefene Hydrochloride (chemical purity 97.2%, assay82.6%) was suspended in 30 ml of water. The mixture was heated up andthe solid dissolved completely at 80° C. Organic volatiles were removedby vacuum distillation. The solution was cooled down to 50° C.

At 50° C., Nalmefene Hydrochloride dihydrate was added as seeding. Themixture was maintained at 50° C. for 3 hours and then allowed to cooldown to 20° C. The suspension was maintained under stirring at 20° C.for around 2.5 days. The solid was filtered and washed with acetone (20ml). The wet product was dried overnight under vacuum at 30° C. yielding11.5 g of Nalmefene hydrochloride dihydrate (chemical purity 99.78%,water content 8.78% w/w as measured by Karl Fisher titration).

1.2 Properties of the Dihydrate

In the TGA (FIG. 1) about 10 mg of sample was heated 10°/min in an openpan under nitrogen flow. The thermogram shows a weigh-loss of about 8.5%starting at 0, room temperature and ending at 125-150° C.

DVS experiments were performed at 25° C. and at 40° C. The shape of thecurves were the same at the two temperatures; the curve at 40° C. isshown in FIG. 2. The dihydrate is retained at relative humidity of10-95%. Adsorption to the surface at high relative humidity is less than0.2%. Desorption of the crystal water occurs slowly under 10% RH. TheDVS-curve however shows complete rehydration after drying at 0% RH, thusthe crystal lattice is retained by this treatment.

X-ray powder diffractogram for Nalmefene hydrochloride dihydrate asobtained using Cu K_(α1) radiation is shown in FIG. 3. The diffractogramis measured in reflection mode in the range 5-40°2θ. It is characterisedby XRPD reflections at 8.99, 10.63, 15.24, 16.55 and 17.20°2θ (±0.1°2θ).

Example 2 2.1a Preparation of the Monohydrate

25 g of Nalmefene hydrochloride (chemical purity 99.24, assay 84.1) wassuspended in 32 ml of water. The mixture was heated up to 80° C. Vacuumwas applied to distill low boiling organic solvents. The solution wascooled down to 20° C. in one hour using a linear ramp. The suspensionwas maintained under stirring for two hours and then further cooled to4° C. in one hour and maintained under stirring at this temperature forone additional. The solid was filtered and washed with 25 ml of acetone.The wet solid was dried overnight under vacuum at 30° C. yielding 13.5 gof Nalmefene hydrochloride monohydrate (water content 4.74% w/w asmeasured by Karl Fisher titration, yield 61%).

2.1b Preparation of the Monohydrate

In a jacketed reactor nalmefene hydrochloride (72.3 g) and water (100ml) were charged. The suspension was heated up to 85° C. obtaining asolution. Nitrogen flow was applied. The solution was cooled down to 60°C. in around 50 minutes and then kept at this temperature for 10minutes. The product started to precipitate at 60° C. The suspension wasfurther cooled to 55° C. and maintained at 55° C. for 10 minutes. Thesuspension was cooled to 8° C. in around one hour and maintained at thattemperature for 30 minutes before isolation. The solid was filtered andwashed with 83 ml of acetone. The solid was dried yielding 48.6 g ofnalmefene hydrochloride monohydrate.

2.2 Properties of the Monohydrate

In the TGA (FIG. 4) about 5 mg of sample was heated 10°/min in an openpan under nitrogen flow. The thermogram showed a weigh-loss of about 4%starting at room temperature and ending at 100-110° C.

DVS experiments were performed at 25° C. and at 40° C. The shape of thecurves was the same, only the curve at 40° C. is shown (FIG. 5).

Most of the water of hydration (4%) was absorbed at 10% RH. Then theweight stepwise increased with the humidity up to 4.3% at 50% RH, but at60% RH it suddenly increased to 6.9% and then again stepwise increasedto 7.3% at 95% RH. The amounts here are given as % weigh increaserelative to dry, thus the weight gain corresponding to monohydrate was4.8% and a 1.5 hydrate corresponds to a gain of 7.2%. The curvetherefore showed that the water content of the monohydrate was notconstant but changes with the relative humidity.

X-ray powder diffractogram (FIG. 6) for Nalmefene hydrochloridemonohydrate as obtained using Cu Kα1 radiation is shown in FIG. 6. Thediffractogram is measured in reflection mode in the range 5-40°2θ. It ischaracterised by XRPD reflections at 7.39, 11.33, 11.52, 17.70 and24.27°2θ (±0.1°2θ).

Example 3 Preparation of Nalmefene Hydrochloride Dihydrate

Crude Nalmefene hydrochloride (7.67 Kg, assay 93.9%) and water (8.6liter) were charged into a suitable reactor. The suspension was heatedup to 80° C. until the substrate completely dissolved. Vacuum was thenapplied to remove organic solvents. The resulting solution was thenfiltered through a 0.65 μm cartridge and then diluted with water (2.1liter) used to rinse the reactor and pipelines. The solution was cooleddown to 50° C. and 7 g of Nalmefene hydrochloride dihydrate seedingmaterial was added. The mixture was cooled down to 0-5° C. in one hourunder efficient stirring and then maintained under stirring for oneadditional hour. The solid was filtered and washed with acetone. The wetproduct was dried at 25° C. under vacuum to provide Nalmefenehydrochloride dihydrate (5.4 Kg; yield 73%) with a chemical purity of99.89% (HPLC).

The particle size of the so obtained Nalmefene hydrochloride dihydratewas determined by Laser Diffraction using a Malvern Mastersizer Sinstrument. Particle size distribution is reported in the table below:

D10 D50 D90 14 μm 122 μm 287 μm

Example 4 Recovery of Nalmefene Hydrochloride

The mother liquors obtained in Example 3 were concentrated under vacuum.Ammonium hydroxide was added till pH 8-9. The mixture was extracted withdichloromethane at a temperature of 30-35° C. The organic phase wasseparated and cooled down to 25° C. Concentrated hydrochloric acid wasadded and the product was allowed to precipitate. The solid was filteredand washed with dichloromethane thus giving 1.35 Kg of Nalmefene HClwith a chemical purity of 98.9%, which can be transformed into thedihydrate applying the procedure described in Example 3.

Example 5 Transformation of Nalmefene HCl into Nalmefene HCl Dihydrateby Re-Slurry

50 g Nalmefene HCl (mixture of monohydrate, acetone solvate anddihydrate) was suspended in 50 ml of water at room temperature. Vacuumwas applied for one hour in order to remove acetone. The suspension wasfurther stirred at room temperature for two hours. The solid wasfiltered and dried under vacuum at 30° C. obtaining 39.9 g of pureNalmefene HCl dihydrate (water content 8.76% w/w as measured by KarlFisher titration).

Example 6 Transformation of Nalmefene HCl into Nalmefene HCl Dihydrateby Re-Slurry

3.6 g of Nalmefene HCl monohydrate was suspended at room temperature in5 ml of water. The suspension was stirred at room temperature. Theconversion to dihydrate was completed after 1.5 hours.

1-7. (canceled)
 8. A method for obtaining a compound having the formula

comprising the steps of: (1) mixing Nalmefene Hydrochloride(17-(cyclopropylmethyl)-4,5-α-epoxy-6-methylenemorphinan-3,14-diolhydrochloride) and an aqueous solution, (2) optionally, heating themixture, (3) optionally, distilling the mixture, (4) stirring themixture until transformation is complete, and (5) isolating the formedsolid.
 9. The method according to claim 8 wherein the mixture in (4) isstirred for at least 1 hour.
 10. The method according to claim 8,wherein the ratio of the aqueous solution used in step (1) ranges fromabout 0.9 ml to about 4 ml aqueous solution/Nalmefene Hydrochloride (g).11. The method according to claim 8, wherein the Nalmefene Hydrochlorideused in step (1) is in a hydrated form.
 12. The method according toclaim 8, wherein the Nalmefene Hydrochloride used in step (1) is in asolvated form or is a mixture of hydrated and solvated forms.
 13. Themethod according to claim 8, wherein stirring is performed in step (2)and/or step (3).
 14. The method according to claim 8, wherein thestirring in step (4) is performed at a temperature of about 0° C. toabout 45° C.
 15. The method according to claim 8, wherein the formedsolid in step (5) is isolated at a temperature from about 0° C. to about20° C. 16-17. (canceled)
 18. A method for obtaining a compound havingthe formula

comprising the steps of: (a) mixing Nalmefene hydrochloride(17-(cyclopropylmethyl)-4,5-α-epoxy-6-methylenemorphinan-3,14-diolhydrochloride) and an aqueous solution, (b) heating the mixture of step(a) to obtain a substantially homogenous solution, (c) optionally,distilling the mixture obtained in step (b), (d) cooling the solutionobtained in step (b) or step (c), subsequently seeding with Nalmefenehydrochloride, and (e) isolating the formed solid.
 19. The methodaccording to claim 18, wherein the amount of aqueous solution used instep (a) ranges from about 0.9 ml to about 4 ml aqueoussolution/Nalmefene hydrochloride (g).
 20. The method according to claim18, wherein heating in step (b) is performed to reach a temperature ofabout 50° C. to about 100° C.
 21. The method according to claim 18,wherein the solution in step (d) is cooled to a temperature between 40to 50° C. and seeding is performed at that temperature.
 22. The methodaccording to claim 18, wherein the amount of seed crystal added in step(d) is from about 1/2000 (w/w) of seed crystal of Nalmefenehydrochloride/Nalmefene hydrochloride added in step (a).
 23. The methodaccording to claim 18, wherein the Nalmefene used for seeding isNalmefene hydrochloride dihydrate.
 24. (canceled)
 25. The methodaccording to claim 18, wherein the mixture obtained in step (d)comprising the seed crystal(s), is further subjected to: (d′) furthercooling the mixture to temperature of about 0-5° C. over a time periodof about 45 minutes or more, and (d″) thereafter maintaining the mixtureat a temperature of about 0-5° C. for about 45 minutes or more, beforeisolating the formed solid according to step (e).
 26. The methodaccording to claim 18, wherein the solid formed is isolated at atemperature of about 0-5° C. in step (e).
 27. (canceled)
 28. The methodaccording to claim 18, wherein the obtained compound has the followingparticle size distribution: D90 equal to or below 400 μm, D50 equal toor below 200 μm, D10 equal to or below 50 μm, with ratio D90/D50 equalto or below 2.5; as measured under the conditions given herein. 29.(canceled)
 30. The method according to claim 8 further comprising thesteps of: (i) optionally, distilling the mother liquors, (ii)basification of the mother liquors obtained in step (i) above or step(5) of claim 8, (iii) extracting the mixture with a suitable organicsolvent, (iv) adding hydrogen chloride, and (v) isolating the formedsolid.
 31. The method according to claim 30 wherein the basification instep (ii) is performed until the pH is in the range of 8-10.
 32. Themethod according to claim 31, wherein the basification in step (ii) isperformed until the pH is in the range of 8-9.
 33. (canceled)
 34. Themethod according to claim 31, wherein the solvent used in the extractionstep (iii) is selected from the group consisting of halogenatedhydrocarbons, ethers, esters, and ketones. 35-46. (canceled)
 47. Themethod according to claim 8, wherein the stirring in step (4) isperformed at a temperature of about 20° C. to about 40° C.
 48. Themethod according to claim 18, wherein heating in step (b) is performedto reach a temperature of about 50° C. to about 90° C.
 49. The methodaccording to claim 18, wherein heating in step (b) is performed to reacha temperature of about 70° C. to about 85° C.
 50. The method accordingto claim 18 further comprising the steps of: (i) optionally distillingthe mother liquors, (ii) basification of the mother liquors obtained instep (i) above or step (e) of claim 18, (iii) extracting the mixturewith a suitable organic solvent, (iv) adding hydrogen chloride, and (v)isolating the formed solid.
 51. The method according to claim 50 whereinthe basification in step (ii) is performed until the pH is in the rangeof 8-10.
 52. The method according to claim 51, wherein the basificationin step (ii) is performed until the pH is in the range of 8-9.
 53. Themethod according to claim 51, wherein the solvent used in the extractionstep (iii) is selected from the group consisting of halogenatedhydrocarbons, ethers, esters, and ketones.